ATIII is a major inhibitor of enzymes in the coagulation cascade, including thrombin (Rosenberg and Damus, (1973) J. Biol. Chem., 248, 6490-6505) and factor Xa (fXa) (Kurachi et al., (1976) Biochemistry, 15, 373-377). Many hereditary mutations in ATIII have been identified that promote hypercoagulability because of unchecked activity of the coagulation enzymes (Reviewed in van Boven and Lane, (1997) Semin. Hematol., 34, 188-204). Acquired deficiencies of ATIII can also occur with negative repercussions on hemostasis, as for example during septic disseminated intravascular coagulopathy (DIC) (Bick et al., (1980) Am. J. Clin. Path., 73, 577-583); (Buller and Cate, (1989) Am. J. Med., 87, 44S-48S); (Damus and Wallace, (1989) Thromb. Res., 6, 27); (Hellgren et al., (1984) Intensive Care Med., 10, 23-28); (Lammle et al., (1984) Am J Clin Patlhol, 82, 396-404); (Mammen et al., (1985) Semin. Thromb. Hemost., 11, 373-383). In contrast, hemorrhage resulting from excess inhibition of blood coagulation by ATIII can occur in the presence of pharmaceutical heparin, which is frequently used to treat and prevent hypercoagulable states (Mant et al., (1977) Lancet, 1, 1133-1135).
ATIII is regulated in part by elastases and proteases that cleave ATIII (Jochum et al., (1981) Hoppe-Seyler's Z. Physiol. Chem. 362, 103-112; Carrell and Owen, (1985) Nature, 317, 730-732; Jordan et al., (1987) Science, 237, 777-779; Mast et al., (1991) J. Biol. Chem. 266, 15810-15816), preventing ATIII from inhibiting thrombin, factor Xa, and other activated coagulation factor targets.